Carboxylic acid esters LiAlH4 reduction

Alcohols are among the most versatile of all organic compounds. They occur widely in nature, are important industrial 7, and have an unusually rich chemistry. The most widely used methods of alcohol synthesis start with carbonyl compounds. Aldehydes, ketones, esters, and carboxylic acids are reduced by reaction with LiAlH4. Aldehydes, esters, and carboxylic acids yield primary alcohols (RCH2OH) on reduction ketones yield secondary alcohols (R2CHOH). 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

However, the most important methods for preparing alcohols are catalytic hydrogenation (H2/Pd-C) or metal hydride (NaBH4 or LiAlH4) reduction of aldehydes, ketones, carboxylic acids, acid chlorides and esters (see Sections 5.7.15 and 5.7.16), and nucleophilic addition of organometalhc reagents (RLi and RMgX) to aldehydes, ketones, acid chlorides and esters (see Sections 5.3.2 and 5.5.5). 

A total synthesis of dihydrolycorine (85), y-lycorane (87) and 8-lyco-rane (92), has been achieved starting from the indanone carboxylic acid 77. This, in turn, was obtained, like the tetralone ester 76, from the known anhydride (75) via Friedel-Crafts cyclization of the monomethyl esters obtained from 75 by treatment with 1 mole of methanol. Reduction of the methyl ester of 77 (LiAlH4), followed by Mn02 oxidation,... 

Piperidine 141 was synthesized from the Barton-McCombie reaction <75JCSP11574> of 142 which gave the expected amido-ester (96 %) as a 3 2-mixture of diastereomers. The mixture was hydrolyzed to the corresponding carboxylic acid which, upon thermal decarboxylation, gave the desired /V-bcnzyl lactam (85% overall yield) as a single diastereomer whose structure was unequivocally established by a single-crystal X-ray analysis. Reduction of the lactam with LiAlH4 (81%) followed by debenzylation via... 

Selective reduction of functional groups can be achieved by chemical modification of the LiALH4 for example, lithium tri(t-butoxy)aluminium hydride [LiAIH(t-OBu)3] is a more selective reagent, and reduces aldehydes and ketones, but slowly reduces esters and epoxides. Nitriles and nitro groups are not reduced by this reagent. Carboxylic acids can be converted into the aldehyde via acid chloride with lithium tri(tert-butoxy) aluminium hydride at a low temperature (—78°C). The nitro compounds are not reduced under this condition. Thus, selective reduction of 3,5-dinitrobenzoic acid (6.45) to 3,5-dinitrobenzaldehyde (6.47) can be achieved in two steps. First, 6.45 is converted into 3,5-dinitrobenzoyl chloride (6.46) and then LiAlH(t-OBu)3 reduction of 6.46 gives 6.47. 

An alternate route to fluoroolefins relies upon the ease of reduction of difluoroolefins(18). Reduction of 114 with sodium bis(2-methoxyethoxy)aluminum hydride (Scheme 35) afforded the fluoroolefins 115 and 116 considerably enriched with the (E)-isomer 116. In a complementary reaction, reduction of the allylic alcohol 117 with LiAlH4 afforded selectively the (Z)-isomer 118. The difluoromethacrylic acid (121) was prepared in similar manner from 120 (Scheme 36) (53 for related examples see references 75 and 76). Under more forcing conditions, further reduction afforded 3-fluoromethacrylic acid 122. Of more general use is the reaction of 120 with Grignard reagents whereupon the 1,4-addition elimination mechanism offers an entry into a-difluoromethylene substituted aliphatic and aromatic carboxylic acids 123. Ester enolates (125) have been shown to add to trifluoropropene (124) forming the difluoroolefins (126) (Scheme 37) (54). 

The reduction of carboxylic acids or esters requires very powerful reducing agents such as lithium aluminum hydride (LiAlH4) or sodium (Na) metal. Aldehydes and ketones are easier to reduce, so they can use sodium borohy-dride (NaBH4). Examples of these reductions are shown in Figure 3-13. 

NaBH4 is superior to LiAlH4 in selective reductions. In "water or methanol soln., it is an effective reagent for the conversion of aldehydes and ketones to the corresponding alcohols. Aoid chlorides are reduced to prim, alcohols in non-aq. media, but carboxylic acids, anhydrides, esters and nitriles are practically unaffected.—E Cinnamaldehyde —> cinnamyl alcohol. Y 97%.—n-Butyryl chloride —n-butanol Y 81%. (F. e. s. S. W. Chaikin, W. G-. Brown, Am. Soc. 71,122 (1949) s. a. H. Heusser et al., Helv. 33, 1093 (1950).)... 

The target molecule is a primary alcohol, which can be prepared 1 reduction of an aldehyde, an ester, or a carboxylic acid. LiAlH4 is need for the ester and carboxylic acid reductions. 1... 

Borane reduces esters very slowly and ketones or aldehydes are selectively reduced in the presence of esters. The most widely used application of borane is for the selective reduction of carboxylic acids, even in the presence of halides, esters, nitriles, and ketones.200 since LiAlH4 reduces both acids and esters and NaBH4 does not reduce acids (and often reduces esters with difficulty), borane is the reagent of choice for selective reduction of carboxylic acids in the presence of an ester group. The reduction occurs without racemization of adjacent chiral centers, as in the borane reduction of (-)-malic acid to generate (5)-l,2,4-butanetriol in 92% yield.201 Seki and Kondo s reduction of the acid moiety in 173 to alcohol 174 (in a synthesis of orally active carbapenams), without reduction of the benzylthio or ester groups also demonstrates this selectivity.202 Borane can reduce imides to give an amine.203 Borane also reduces epoxides at the less hindered carbon when mixed with catalytic amounts of sodium borohydride.204... 

Reduction with complex metal hydrides. Useful reduction systems are those nvolving NaBHy 68 and LiAlH4/69. Synthesis of chiral a-hydroxy carboxylic acids -on take advantage of forming esters or amides with chiral auxiliaries. Typical examples are i picted by 70, 3 71,and 72. ... 

Scheme 9.109. A cartoon representation of the reduction of a carboxylic acid (L = OH), an ester (L = OR ), and an acid chloride (L = Cl) of 2-phenylethanoic acid (2-phenylacetic acid, a-phenylacetic acid, C6H5CH2CO2H) to the corresponding alcohol, 2-phenylethanol (C6H5CH2CH2OH) with lithium aluminum hydride (LiAlH4) in ether [(CH3CH2)20] solution.

Fischer Esterification—Acid-Catalyzed Conversion of Carboxylic Acids to Esters 848 Conversion of Carboxylic Acids to Amides with DCC 850 Acid-Catalyzed Hydrolysis of an Ester to a Carboxyhc Acid 851 Base-Promoted Hydrolysis of an Ester to a Carboxyhc Acid 852 Amide Hydrolysis in Base 856 Hydrolysis of a Nitrile in Base 864 Reduction of a Nitrile with LiAlH4 865 Reduction of a Nitrile with DIBAL-H 866... 

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